Cocaine vaccine for the treatment of cocaine dependence in methadone-maintained patients: a randomized, double-blind, placebo-controlled efficacy trial

Abstract

Context: Cocaine dependence, which affects 2.5 million Americans annually, has no US Food and Drug Administration-approved pharmacotherapy.

Objectives: To evaluate the immunogenicity, safety, and efficacy of a novel cocaine vaccine to treat cocaine dependence.

Design: A 24-week, phase 2b, randomized, double-blind, placebo-controlled trial with efficacy assessed during weeks 8 to 20 and follow-up to week 24.

Setting: Cocaine- and opioid-dependent persons recruited from October 2003 to April 2005 from greater New Haven, Connecticut.

Participants: One hundred fifteen methadone-maintained subjects (67% male, 87% white, aged 18-46 years) were randomized to vaccine or placebo, and 94 subjects (82%) completed the trial. Most smoked crack cocaine along with using marijuana (18%), alcohol (10%), and nonprescription opioids (44%).

Intervention: Over 12 weeks, 109 of 115 subjects received 5 vaccinations of placebo or succinylnorcocaine linked to recombinant cholera toxin B-subunit protein. Main Outcome Measure Semiquantitative urinary cocaine metabolite levels measured thrice weekly with a positive cutoff of 300 ng/mL.

Results: The 21 vaccinated subjects (38%) who attained serum IgG anticocaine antibody levels of 43 microg/mL or higher (ie, high IgG level) had significantly more cocaine-free urine samples than those with levels less than 43 microg/mL (ie, low IgG level) and the placebo-receiving subjects during weeks 9 to 16 (45% vs 35% cocaine-free urine samples, respectively). The proportion of subjects having a 50% reduction in cocaine use was significantly greater in the subjects with a high IgG level than in subjects with a low IgG level (53% of subjects vs 23% of subjects, respectively) (P = .048). The most common adverse effects were injection site induration and tenderness. There were no treatment-related serious adverse events, withdrawals, or deaths.

Conclusions: Attaining high (>or=43 microg/mL) IgG anticocaine antibody levels was associated with significantly reduced cocaine use, but only 38% of the vaccinated subjects attained these IgG levels and they had only 2 months of adequate cocaine blockade. Thus, we need improved vaccines and boosters. Trial Registration clinicaltrials.gov Identifier: NCT00142857.

Figure 1

Flow chart of study participants

Figure 2. IgG responses to the Cocaine-CTB vaccine was highly variable

Among the 55 immunized with the cocaine vaccine (at weeks 0, 2, 4, 8, and 12), 21 (38%) attained levels greater than 43 µg/ml as shown in solid lines. Of those, 3 three were highly responsive subjects, with one having >60 µg/ml of IgG anti-cocaine antibody even before immunization. Two made a vigorous response after the 2nd injection (week 4 samples). Eight subjects made over 43 µg/ml after 3 injections, and 8 required 4 or more injections of antigen to make a response that exceeded 43 µg/ml of anti-cocaine IgG. Antibody responses for the remaining 34 subjects are in dotted lines. The number of subjects at weeks 2, 4, 8, 12, 16, 20, 24 are respectively: 55, 55, 55, 55, 54, 51, 51.

Figure 3. Mean weekly cocaine-free urines by medication condition for weeks 1–20

Green triangles line represents placebo, black squares line active cocaine vaccine recipients with IgG levels below 43 ug/ml (Lo IgG), and red diamonds line active cocaine vaccine recipients with IgG levels > 43 ug/ml (Hi IgG). The x axis is the number of weeks since the first vaccination and the y axis represents 100 times the weekly mean proportion of cocaine-free urines for the three treatment groups. Standard errors are not shown for clarity, but range from +/−5% at any time-point. The Hi IgG group had significantly more cocaine-free urines than the other two groups during weeks 9 to 16 (t=2.26; P<0.03) and a significantly greater increase in cocaine-free urines than the other two groups from weeks 1 to 16 on HLM analysis (Z= 4.8; P<0.01). The three groups did not differ in cocaine-free urines during weeks 17 to 20.

Figure 4. Scatter-plot of peak antibody response by % cocaine-negative urines

Filled diamonds are individual vaccinated subject values for peak antibody response (typically at week 16) plotted against their percentage of cocaine-negative urines using the Preston criteria for new uses of cocaine during weeks 8 through 20. The graph is divided into quadrants by a horizontal line at the 43 ug/ml antibody and a vertical line at 50% cocaine free urines. The numbers in each quadrant represent the number of subjects in each quadrant. The proportion of subjects who had 50% or more cocaine free urines is significantly greater in those with anti-cocaine IgG antibody > 43 ug/ml than those with lower antibody levels (Fishers test, P<0.04).